Cancer immunotherapy relies on the modulation of the immune system to increase recognition and response against tumour cells. Such modulation can be achieved by multiple mechanisms including the activation of co-stimulatory molecules present on immune cells or through the inhibition of co-inhibitory receptors. The activation of an immune response is a complex mechanism involving numerous cell populations like antigen-presenting cells important for the initiation of the antigen-specific response and effector cells responsible for tumour cell destruction. The mechanisms modulating the activity of effector cells like cytotoxic T cells are numerous and represent target of choice in the context of cancer immunotherapy.
TIGIT (T cell Immunoreceptor with Ig and ITIM domains), also called WUCAM, VSIG9 or Vstm3, is a co-inhibitory receptor preferentially expressed on NK, CD8+ and CD4+ T cells as well as on regulatory T cells (Treg cells, or simply “Tregs”). TIGIT is transmembrane protein containing a known ITIM domain in its intracellular portion, a transmembrane domain and an immunoglobulin variable domain on the extracellular part of the receptor. Several ligands were described to bind to TIGIT receptor with CD155/PVR showing the best affinity followed by CD113/PVRL3 and CD112/PVRL2 (Yu et al. (2009) Nat. Immunol. 10:48.). DNAM/CD226, a known co-stimulatory receptor also expressed on NK and T cells competes with TIGIT for CD155 and CD112 binding but with a lower affinity, which suggests a tight control of the activation of these effector cells to avoid uncontrolled cytotoxicity against normal cells expressing CD155 ligand.
TIGIT expression is increased on tumour infiltrating lymphocytes (TILs) and in disease settings such as HIV infection. TIGIT expression marks exhausted T cells that have lower effector function as compared to TIGIT negative counterparts (Kurtulus et al. (2015) J. Clin. Invest. 276:112; Chew et al. (2016) Plos Pathogens. 12). Conversely, Treg cells that express TIGIT show enhanced immunosuppressive activity as compared to TIGIT negative Treg population (Joller et al. (2014) Immunity. 40:569).
Like other co-inhibitory receptors (PD1 or CTLA4) expressed on T cells that have been proven to be relevant target for immunotherapy and for which antagonistic antibodies have been approved for the treatment of human cancer, the development of antagonistic anti-TIGIT antibody may help to turn-on the immune system and better fight cancer cells. It has been suggested that antagonistic anti-TIGIT antibodies in monotherapy or in combination with a-PD1 antibody could achieve strong anti-tumour efficacy in preclinical models (Johnston et al. (2014) Cancer Cell 26:1; WO2016/028656; US2016/0176963; US2016/0376365, all of which are incorporated herein by reference).
Thus, antagonistic antibodies specific for TIGIT that could inhibit TIGIT receptor activity represent an opportunity to decrease the immunosuppressive effect associated with tumour microenvironments and thereby increase antitumor immune response against tumour cells.